title: LnPO4 nanoparticles doped with Ac-225 and sequestered daughters for targeted alpha therapy.
abstract: For targeted alpha therapy (TAT) with 225Ac, daughter radioisotopes from the parent emissions should be controlled. Here, we report on a second-generation layered nanoparticle (NP) with improved daughter retention that can mediate TAT of lung tumor colonies. NPs of La3+, Gd3+, and 225Ac3+ ions were coated with additional layers of GdPO4 and then coated with gold via citrate reduction of NaAuCl4. MAb 201b, targeting thrombomodulin in lung endothelium, was added to a polyethylene glycol (dPEG)-COOH linker. The NPs:mAb ratio was quantified by labeling the mAb with 125I. NPs showed 30% injected dose/organ antibody-mediated uptake in the lung, which increased to 47% in mice pretreated with clodronate liposomes to reduce phagocytosis. Retention of daughter 213Bi in lung tissue was more than 70% at one hour and about 90% at 24 hours postinjection. Treatment of mice with lung-targeted 225Ac NP reduced EMT-6 lung colonies relative to cold antibody competition for targeting or phosphate-buffered saline injected controls. We conclude that LnPO4 NPs represent a viable solution to deliver the 225Ac as an in vivo α generator. The NPs successfully retain a large percentage of the daughter products without compromising the tumoricidal properties of the α-radiation.
authors.affiliation: 1 Department of Chemistry and University of Missouri Research Reactor, University of Missouri , Columbia, Missouri.
authors.forename: Mark F
authors.initials: MF
authors.lastname: McLaughlin
authors.forename: David
authors.initials: D
authors.lastname: Robertson
authors.forename: Paul H
authors.initials: PH
authors.lastname: Pevsner
authors.forename: Jonathan S
authors.initials: JS
authors.lastname: Wall
authors.forename: Saed
authors.initials: S
authors.lastname: Mirzadeh
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Kennel
mesh_terms: D000186:Actinium / Q000008:administration & dosage* / Q000737:chemistry; D000512:Alpha Particles / Q000627:therapeutic use*; D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000737:chemistry; D005260:Female; D028581:Lanthanoid Series Elements / Q000008:administration & dosage* / Q000737:chemistry; D008168:Lung / Q000000981:diagnostic imaging / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D053758:Nanoparticles / Q000008:administration & dosage*; D036103:Nanotechnology / Q000379:methods; D010710:Phosphates / Q000008:administration & dosage* / Q000737:chemistry; D011877:Radionuclide Imaging; D019275:Radiopharmaceuticals / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics
chemical_list: D000911:Antibodies, Monoclonal; D028581:Lanthanoid Series Elements; D010710:Phosphates; D019275:Radiopharmaceuticals; D000186:Actinium